PARP inhibitor YCH1899 activates type I interferon signaling and synergizes with STING agonists in BRCA-proficient...

Poly(ADP-ribose) polymerase (PARP) inhibitors are highly effective in BRCA-deficient tumors, yet their therapeutic benefit in BRCA-proficient cancers remains limited. Here, we demonstrate that YCH1899, a next-generation, resistance-overcoming PARP inhibitor, elicits significantly stronger type I interferon signaling than currently approved PARP inhibitors in BRCA-proficient tumor cells. Mechanistically, YCH1899 facilitates the accumulation of cytosolic DNA, thereby robustly activating the cGAS-STING-IRF3 pathway. Consequently, YCH1899 exhibits potent inhibitory effects on the growth of various BRCA-proficient tumors in a STING-dependent manner and enhances the infiltration of CD8⁺ T cells within the tumor microenvironment. To identify tumor-intrinsic regulators of this immune response, we conducted in vivo CRISPR screens, which revealed USP20 as a prominent regulator. The genetic ablation of USP20 markedly diminished the antitumor immunity induced by YCH1899 in vivo, suggesting that USP20 may serve as a potential predictive biomarker. Furthermore, combining YCH1899 with STING agonists synergistically amplifies interferon pathway activation, driven by enhanced phosphorylation of IRF3 at Ser173, resulting in superior tumor control and profound immune cell infiltration and activation within the tumor microenvironment. Collectively, our findings establish YCH1899 as a potent PARP inhibitor capable of extending clinical benefit to BRCA-proficient cancers and provide a rationale for its clinical combination with STING agonists to elicit robust antitumor immunity, even in patients resistant to PARP inhibitors.